2. Academic Validation
  3. Short-chain aurachin D derivatives are selective inhibitors of E. coli cytochrome bd-I and bd-II oxidases

Short-chain aurachin D derivatives are selective inhibitors of E. coli cytochrome bd-I and bd-II oxidases

  • Sci Rep. 2021 Dec 13;11(1):23852. doi: 10.1038/s41598-021-03288-7.
Melanie Radloff 1,  Isam Elamri 2,  Tamara N Grund 1,  Luca F Witte 1,  Katharina F Hohmann 2,  Sayaka Nakagaki 3,  Hojjat G Goojani 4,  Hamid Nasiri 5,  Hideto Miyoshi 6,  Dirk Bald 4,  Hao Xie 1,  Junshi Sakamoto 3,  Harald Schwalbe 7,  Schara Safarian 8
Affiliations

Affiliations

  • 1 Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438, Frankfurt am Main, Germany.
  • 2 Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Goethe-University Frankfurt Am Main, Max-von Laue-Straße 7, 60438, Frankfurt am Main, Germany.
  • 3 Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Kawazu 680-4, Iizuka, Fukuoka-ken, 820-8502, Japan.
  • 4 Department of Molecular Cell Biology, Amsterdam Institute of Molecular and Life Sciences, Faculty of Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
  • 5 Department of Cellular Microbiology, University Hohenheim, 70599, Stuttgart, Germany.
  • 6 Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
  • 7 Center for Biomolecular Magnetic Resonance, Institute of Organic Chemistry and Chemical Biology, Goethe-University Frankfurt Am Main, Max-von Laue-Straße 7, 60438, Frankfurt am Main, Germany. schwalbe@nmr.uni-frankfurt.de.
  • 8 Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438, Frankfurt am Main, Germany. schara.safarian@biophys.mpg.de.
PMID: 34903826 DOI: 10.1038/s41598-021-03288-7
Abstract

Cytochrome bd-type oxidases play a crucial role for survival of pathogenic bacteria during Infection and proliferation. This role and the fact that there are no homologues in the mitochondrial respiratory chain qualify cytochrome bd as a potential antimicrobial target. However, few bd oxidase selective inhibitors have been described so far. In this report, inhibitory effects of Aurachin C (AurC-type) and new Aurachin D (AurD-type) derivatives on oxygen reductase activity of isolated terminal bd-I, bd-II and bo3 oxidases from Escherichia coli were potentiometrically measured using a Clark-type electrode. We synthesized long- (C10, decyl or longer) and short-chain (C4, butyl to C8, octyl) AurD-type compounds and tested this set of molecules towards their selectivity and potency. We confirmed strong inhibition of all three terminal oxidases for AurC-type compounds, whereas the 4(1H)-quinolone scaffold of AurD-type compounds mainly inhibits bd-type oxidases. We assessed a direct effect of chain length on inhibition activity with highest potency and selectivity observed for heptyl AurD-type derivatives. While Aurachin C and Aurachin D are widely considered as selective inhibitors for terminal oxidases, their structure-activity relationship is incompletely understood. This work fills this gap and illustrates how structural differences of Aurachin derivatives determine inhibitory potency and selectivity for bd-type oxidases of E. coli.

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